Mangiapane scored on a scramble in front on the power play at 7:54 to make it 2-1. Tippett challenged for goaltender interference by Tkachuk, but the goal stood after video review, and the Oilers received a minor penalty for delay of game.
McDavid scored on the power play at 17:11 when he tipped a shot from Tyson Barrie to extend the lead to 3-1.
"We all know what type of player he is," Flames defenseman Mark Giordano said of McDavid. "But we go back to the quality of chances, you can't give a great player like him those looks. He had a lot of time and space, a lot of time to make his mind up what he was going to do, and he made us pay. We're a whole lot better than that. I thought yesterday we did a great job on the top two players on their side (neither McDavid nor Draisaitl had a point), and tonight was a total opposite."
McDavid scored 1:06 into the second period off a rush down the right side for a 4-1 lead and completed the hat trick at 8:12 to make it 5-1.
"Obviously, he was really, really good tonight," Flames coach Geoff Ward said. "I thought we did a real good job on him last night, and tonight he was good. Good players, they have the ability to do that. Saying that for us, we still need to be aware of that, and when you give a good player as much time and space as we did tonight, that's what happens."
Nugent-Hopkins made it 6-1 on the power play at 12:38, and Josh Archibald scored 36 seconds into the third period for the 7-1 final.
"To be able to win both and in regulation, it's big for us," McDavid said. "But it's still early on in the year, there's lots of hockey left. We're playing well and we need to keep winning games."
NOTES: Oilers defenseman Slater Koekkoek sustained an upper-body injury in a collision with Flames forward Sam Bennett 14 seconds into his first shift in the first period. Edmonton forward Kailer Yamamoto sustained an undisclosed injury in the third period. Each will be reevaluated Sunday, Tippett said. … It was McDavid's second natural hat trick in the NHL (Oct. 4, 2017, also against the Flames). … Barrie has 14 points (three goals, 11 assists) in his past 12 games. … Bennett got 14:19 of ice time after playing 6:30 and being benched in the third period Friday. He had requested a trade through his agent and was a healthy scratch Feb. 4. … Calgary forward Glenn Gawdin had four hits in 6:04 in his NHL debut. … It was the second straight start Markstrom was pulled after allowing five goals. He was replaced by Rittich at 7:47 of the third period in a 5-1 loss to the Vancouver Canucks on Wednesday.